The nitrate ester, glyceryl trinitrate (GTN), or nitroglycerin, has been used as a vasodilator in the treatment of angina pectoris for over a hundred years, and the dominant, contemporary belief is that GTN exerts its therapeutic effect through in vivo release of nitric oxide (NO). Other organic nitrates (nitrate esters), such as isosorbide dinitrate, have also been identified as effective and clinically important vasodilators. NO itself has been identified as Endothelium Derived Relaxing Factor (EDRF) and several classes of compounds, for example nitrosothiols, in addition to organic nitrates, have been proposed as NO donors or NO prodrugs.
Several organic nitrates, in which an alkyl mononitrate is appended to a moiety with analgesic properties, such as aspirin (ASA) or a Non-Steroidal Anti-Inflammatory Drug (NSAID) have been reported as analgesics which possess reduced gastro-intestinal irritation and ulceration properties, purportedly through release of NO. The combination of the vasodilator nitroglycerin with opioid analgesics such as morphine, has been suggested to be effective in the management of both surgical and cancer pain. However, no attempt has been made to develop organic nitrates themselves as analgesic agents, that is, organic nitrates that do not rely on an ASA or NSAID moiety, nor an opiate, for analgesic properties. Thus, there is a need for synthetic organic nitrates as new and useful therapeutic agents for treatment and mitigation of pain associated with disease states and chemotherapy of those disease states.